Human lipoxygenases (LOXs) are the enzymes participating in the metabolism of the polyunsaturated fatty acids and catalyzing their oxidation to a variety of eicosanoids, which as the secondary signal transducers have a major impact on human homeostasis. They are involved in many diseases such as inflammatory responses, cancers, cardiovascular and kidney diseases, neurodegenerative disorders and metabolic syndrome[1].PD146176 (NSC168807), a 15-Lipoxygenase (15-LO) inhibitor, inhibits rabbit reticulocyte 15-LO (Ki=197 nM, IC50=0.54 μM). PD146176 reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice[2]. In intact IC21 cells transfected with human 15-LO, PD146176 inhibits 13-HODE production with an IC50 of 0.81 μM[3]. PD146176 (80 mg/kg; Chowing; 12 weeks) reverses cognitive impairment, brain amyloidosis, and Tau pathology by stimulating autophagy in aged triple transgenic mice[4]. Compared with mice receiving placebo, the group treated with PD146176 manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity[5].
PD146176 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human bronchial epithelial cells
1 mM
10 days
To evaluate the inhibitory effect of PD146176 on IL-13-induced MUC5AC expression. Results showed that PD146176 significantly suppressed IL-13-induced MUC5AC mRNA expression.
Am J Respir Crit Care Med. 2009 May 1;179(9):782-90
DRG neurons
10 µM
15 minutes
To investigate the inhibitory effect of PD146176 on LA-induced calcium responses, results showed that PD146176 significantly reduced the response of DRG neurons to LA.
Br J Pharmacol. 2013 Apr;168(8):1961-74
Human lung macrophages
10 µM
24 hours
To investigate the inhibitory effect of PD146176 on chemokine release induced by LPS and Th2 cytokines. Results showed that PD146176 significantly reduced the release of chemokines induced by LPS and Th2 cytokines.
Br J Pharmacol. 2015 Sep;172(17):4319-30
PD146176 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Alcoholic liver disease model
Intraperitoneal injection
10 mg/kg
Once daily for 7 days
To test the therapeutic effect of PD146176 on alcoholic liver disease, results showed that PD146176 significantly alleviated alcohol-elevated plasma AST and ALT, diminished alcohol-induced liver histopathological changes, inhibited ROS production, and reduced hepatic lipid accumulation.
Sci Rep. 2017 Aug 21;7(1):8976
Rats
Pregnant rats
Intraperitoneal injection
5 mg/kg
Administered 1 h before each exposure for three consecutive days
PD146176 mitigated sevoflurane-induced ferroptosis and subsequent cognitive impairment, reduced elevated MDA levels and significantly reduced iron overload, alleviated inhibition of GPX4 activity, and improved neural density and alignment of the CA1 region of the hippocampus during long-term development.
CNS Neurosci Ther. 2023 Oct;29(10):2972-2985
Sprague Dawley rats
Carrageenan-induced inflammatory pain model
Intraplantar injection
50 µg/50 µL
Single administration, observed for 4 hours
To investigate the effect of PD146176 on inflammatory pain behavior, results showed that PD146176 significantly attenuated carrageenan-induced hyperalgesia.
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